1. health and fitness
2. disease

-----------------DOSAGE FORMS AND STRENGTHS-----Tablets: 75, 100 and 150 mg (3)
HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use DORYX®
(doxycycline hyclate) Delayed-Release Tablets safely and effectively. See Full Prescribing Information for DORYX Tablets. -----------------CONTRAINDICATIONS----------------------Doxycycline is contraindicated in persons who have shown hypersensitivity to
any of the tetracyclines. (4)
®
DORYX (doxycycline hyclate) Delayed-Release Tablets, 75 mg, 100 mg and 150 mg for Oral use. Initial U.S. Approval: 1967
-----------------WARNINGS AND PRECAUTIONS---------•
The use of drugs of the tetracycline class during tooth development (last
half of pregnancy, infancy and childhood to the age of 8 years) may cause
permanent discoloration of the teeth (yellow-gray-brown). (5.1)
•
Clostridium difficile-associated diarrhea: Evaluate patients if diarrhea
occurs. (5.2)
•
Photosensitivity manifested by an exaggerated sunburn reaction has been
observed in some individuals taking tetracyclines. Limit sun exposure. (5.3)
•
Overgrowth of non-susceptible organisms, including fungi, may occur. Re­
evaluate therapy if superinfection occurs. (5.4)
To reduce the development of drug-resistant bacteria and maintain the effectiveness
of doxycycline hyclate and other antibacterial drugs, DORYX Tablets should be
used only to treat or prevent infections that are proven or strongly suspected to be
caused by bacteria. (1)
----------------RECENT MAJOR CHANGES------Dosage Forms and Strengths, added DORYX Tablets 150 mg (3) 06/2008
Geriatric Use, added mg (mEq) sodium for DORYX Tablets 150 mg (8.5)
06/2008
Pharmacokinetics, added food effect wording for DORYX Tablets 150 mg (12.3)
06/2008
How Supplied/Storage and Handling, added DORYX Tablets 150 mg (16)
06/2008
-------------------ADVERSE REACTIONS---------------------­
Adverse reactions observed in patients receiving tetracyclines include anorexia,
nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic
anemia. (6)
---------------INDICATIONS AND USAGE------------------­
DORYX is a tetracycline-class antimicrobial indicated for:
•
•
•
•
•
•
•
•
•
To report SUSPECTED ADVERSE REACTIONS, contact Warner Chilcott
at 1-800-521-8813 and www.wcrx.com or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
Rickettsial infections (1.1)
Sexually transmitted infections (1.2)
Respiratory tract infections (1.3)
Specific bacterial infections (1.4)
Ophthalmic infections (1.5)
Anthrax, including inhalational anthrax (post-exposure) (1.6)
Alternative treatment for selected infections when penicillin is
contraindicated (1.7)
Adjunctive therapy in acute intestinal amebiasis and severe acne (1.8)
Prophylaxis of malaria (1.9)
--------------------DRUG INTERACTIONS--------------------­
•
Patients who are on anticoagulant therapy may require downward
adjustment of their anticoagulant dosage (7.1)
•
Avoid coadministration of tetracyclines with penicillin (7.2)
•
Absorption of tetracyclines is impaired by antacids containing aluminum,
calcium, or magnesium, bismuth subsalicylate and iron-containing
preparations (7.3)
•
Concurrent use of tetracycline may render oral contraceptives less effective
(7.7)
•
Barbiturates, carbamazepine and phenytoin decrease the half-life of
doxycycline
----------------DOSAGE AND ADMINISTRATION---------•
Adults: the usual dose of oral doxycycline is 200 mg on the first day of
treatment (administered 100 mg every 12 hours) followed by a maintenance
dose of 100 mg/day. In the management of more severe infections
(particularly chronic infections of the urinary tract), 100 mg every 12 hours
is recommended. (2.1)
•
--------------------USE IN SPECIFIC POPULATIONS------­
•
Pregnancy Category D (8.1)
•
Tetracyclines are excreted in human milk; however, the extent of absorption
of doxycycline in the breastfed infant is not known. Doxycycline use
during nursing should be avoided if possible. (8.3)
For children above eight years of age: The recommended dosage schedule
for children weighing 100 pounds or less is 2 mg/lb of body weight divided
into two doses on the first day of treatment, followed by 1 mg/lb of body
weight given as a single daily dose or divided into two doses on subsequent
days. For more severe infections up to 2 mg/lb of body weight may be used.
For children over 100 lb, the usual adult dose should be used. (2.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
Patient Labeling.
Revised: June 2008
____________________________________________________________________
FULL PRESCRIBING INFORMATION: CONTENTS*
6
WARNING
1
INDICATIONS AND USAGE
1.1
Rickettsial
Infections
1.2 Sexually Transmitted Infections
1.3 Respiratory Tract Infections
1.4 Specific Bacterial Infections
1.5
Ophthalmic
Infections
1.6 Anthrax, Including Inhalational Anthrax (Post-Exposure)
1.7 Alternative Treatment for Selected Infections when Penicillin
is Contraindicated
1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe
Acne
1.9
Prophylaxis of Malaria
2
DOSAGE AND ADMINISTRATION
2.1 Usual Dosage and Administration
2.2 For Prophylaxis of Malaria
2.3 Inhalation Anthrax (post exposure)
2.4
Sprinkling the tablet over applesauce
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Tooth Development
5.2 Pseudomembranous Colitis
5.3 Photosensitivity
5.4 Superinfection
5.5 Benign Intracranial Hypertension
5.6 Growth and Development
5.7 Antianabolic Action
5.8 Incision and Drainage
5.9 Malaria
5.10 Development of Drug-Resistant Bacteria
5.11 Syphilis Testing
5.12 Laboratory Testing for Long-Term Therapy
7
8
10
11
12
13
15
16
17
ADVERSE REACTIONS
6.1 Gastrointestinal
6.2 Skin
6.3 Renal
6.4 Hypersensitivity Reactions
6.5 Blood
6.6 Benign Intracranial Hypertension
6.7
Thyroid Gland Changes
DRUG INTERACTIONS
7.1
Anticoagulant
Drugs
7.2 Penicillin
7.3 Antacids and Iron Preparations
7.4 Oral Contraceptives
7.5
Barbiturates
and Anti-epileptics
7.6 Penthrane
7.7
Drug/Laboratory Test Interactions
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6
Renal Impairment
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
REFERENCES
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the Full Prescribing Information are not
listed.
1
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 75 mg, 100 mg and 150 mg
1
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of
DORYX and other antibacterial drugs, DORYX should be used only to treat or prevent
infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information are available, they should be considered in
selecting or modifying antibacterial therapy. In the absence of such data, local
epidemiology and susceptibility patterns may contribute to the empiric selection of
therapy.
Doxycycline is a tetracycline-class antimicrobial indicated in the following conditions or
diseases:
1.1
Rickettsial infections
Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever,
rickettsialpox, and tick fevers caused by Rickettsiae.
1.2
Sexually transmitted infections
Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Calymmatobacterium granulomatis. 1.3
Respiratory tract infections
Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydia psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following micro­
organisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumoniae.
1.4
Specific bacterial infections
Relapsing fever due to Borrelia recurrentis. Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). 2
Bartonellosis due to Bartonella bacilliformis.
Because many strains of the following groups of microorganisms have been shown to be
resistant to doxycycline, culture and susceptibility testing are recommended.
Doxycycline is indicated for treatment of infections caused by the following gramnegative microorganisms, when bacteriological testing indicates appropriate
susceptibility to the drug:
Escherichia coli
Enterobacter aerogenes
Shigella species
Acinetobacter species
Urinary tract infections caused by Klebsiella species.
1.5
O
phthalmic infections
Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. 1.6 Anthrax including inhalational anthrax (post-exposure)
Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to
reduce the incidence or progression of disease following exposure to aerosolized Bacillus
anthracis.
1.7
Alternative treatment for selected infections when penicillin is
contraindicated
When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pertenue. Vincent’s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. 1.8
Adjunctive therapy for acute intestinal amebiasis and severe acne
In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides.
In severe acne, doxycycline may be useful adjunctive therapy.
1.9 Prophylaxis of malaria
Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in
short-term travelers (<4 months) to areas with chloroquine and/or pyrimethamine­
sulfadoxine resistant strains. [See DOSAGE AND ADMINISTRATION (2.2) and
PATIENT COUNSELING INFORMATION (17).]
3
2
DOSAGE AND ADMINISTRATION
2.1 Usual Dosage and Administration
THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF
DOXYCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES.
EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED
INCIDENCE OF SIDE EFFECTS.
Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment
(administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg/day.
The maintenance dose may be administered as a single dose or as 50 mg every 12 hours.
In the management of more severe infections (particularly chronic infections of the
urinary tract), 100 mg every 12 hours is recommended.
For children above eight years of age: The recommended dosage schedule for children
weighing 45 kg (100 lb) or less is 4.4 mg/kg (2 mg/lb) of body weight divided into two
doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single
daily dose or divided into two doses on subsequent days. For more severe infections up to
4.4 mg/kg (2 mg/lb) of body weight may be used. For children over 45 kg (100 lb), the
usual adult dose should be used.
Administration of adequate amounts of fluid along with capsule and tablet forms of drugs
in the tetracycline class is recommended to wash down the drugs and reduce the risk of
esophageal irritation and ulceration [see ADVERSE REACTIONS (6.1)].
If gastric irritation occurs, doxycycline may be given with food or milk [see CLINICAL
PHARMACOLOGY (12)].
When used in streptococcal infections, therapy should be continued for 10 days.
Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia
trachomatis: 100 mg by mouth twice a day for 7 days.
Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg
by mouth twice a day for 7 days.
Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline
100 mg by mouth twice a day for 2 weeks.
Syphilis of more than one year’s duration: Patients who are allergic to penicillin should
be treated with doxycycline 100 mg by mouth twice a day for 4 weeks.
Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at
least 10 days.
4
2.2 For prophylaxis of malaria
For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the
recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should
begin 1-2 days before travel to the malarious area. Prophylaxis should be continued daily
during travel in the malarious area and for 4 weeks after the traveler leaves the malarious
area.
2.3 Inhalational anthrax (post-exposure)
ADULTS: 100 mg, of doxycycline, by mouth, twice a day for 60 days.
CHILDREN: weighing less than 45 kg (100 lb) 2.2 mg/kg (1 mg/lb) of body weight, by
mouth, twice a day for 60 days. Children weighing 45 kg (100 lb) or more should receive
the adult dose.
2.4 Sprinkling the tablet over applesauce
DORYX Tablets may also be administered by carefully breaking up the tablet and
sprinkling the tablet contents (delayed-release pellets) on a spoonful of applesauce. The
delayed-release pellets must not be crushed or damaged when breaking up the tablet. Any
loss of pellets in the transfer would prevent using the dose. The applesauce/DORYX
mixture should be swallowed immediately without chewing and may be followed by a
glass of water if desired. The applesauce should not be hot, and it should be soft enough
to be swallowed without chewing. In the event that a prepared dose of
applesauce/DORYX Tablet cannot be taken immediately, the mixture should be
discarded and not stored for later use.
3
DOSAGE FORMS AND STRENGTHS
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 75 mg are white oval tablets
containing yellow pellets and debossed with “D75” on one face and plain on the other.
Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 75 mg
of doxycycline.
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 100 mg are white oval tablets
containing yellow pellets and debossed with “D100” on one face and plain on the other.
Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 100 mg
of doxycycline.
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 150 mg are white, oval scored
tablets containing yellow pellets and debossed with “D1|50” on one face and plain on the
other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to
150 mg of doxycycline.
4
CONTRAINDICATIONS
The drug is contraindicated in persons who have shown hypersensitivity to any of the
tetracyclines.
5
WARNINGS AND PRECAUTIONS
5
5.1
Tooth Development
THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH
DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD
TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF
THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common
during long-term use of the drugs but it has been observed following repeated short-term
courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS,
THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR
ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE),
UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE
CONTRAINDICATED.
5.2
Pseudomembranous Colitis
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including DORYX Tablets, and may range in severity from mild
diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the
colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as
these infections can be refractory to antimicrobial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibiotic
use. Careful medical history is necessary since CDAD has been reported to occur over
two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.
difficile may need to be discontinued. Appropriate fluid and electrolyte management,
protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation
should be instituted as clinically indicated.
5.3
Photosensitivity
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in
some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or
ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and
treatment should be discontinued at the first evidence of skin erythema.
5.4
Superinfection
As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be
discontinued and appropriate therapy instituted.
5.5
Benign Intracranial Hypertension
Bulging fontanels in infants and benign intracranial hypertension in adults have been
reported in individuals receiving tetracyclines. These conditions disappeared when the
drug was discontinued.
6
5.6
Growth and Development
All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease
in fibula growth rate has been observed in prematures given oral tetracycline in doses of
25 mg/kg every six hours. This reaction was shown to be reversible when the drug was
discontinued.
Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal
tissues, and can have toxic effects on the developing fetus (often related to retardation of
skeletal development). Evidence of embryotoxicity also has been noted in animals treated
early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes
pregnant while taking these drugs, the patient should be apprised of the potential hazard
to the fetus.
5.7
Antianabolic Action
The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to
date indicate that this does not occur with the use of doxycycline in patients with
impaired renal function.
5.8
Incision and Drainage
Incision and drainage or other surgical procedures should be performed in conjunction
with antibiotic therapy, when indicated.
5.9
Malaria
Doxycycline offers substantial but not complete suppression of the asexual blood stages
of Plasmodium strains.
Doxycycline does not suppress P. falciparum’s sexual blood stage gametocytes. Subjects
completing this prophylactic regimen may still transmit the infection to mosquitoes
outside endemic areas.
5.10
Development of Drug Resistant Bacteria
Prescribing DORYX in the absence of a proven or strongly suspected bacterial infection
or a prophylactic indication is unlikely to provide benefit to the patient and increases the
risk of the development of drug-resistant bacteria.
5. 11 Syphilis Testing
In venereal disease when coexistent syphilis is suspected, dark-field examinations should
be done before treatment is started and the blood serology repeated monthly for at least 4
months.
5.12 Laboratory Monitoring for Long-Term Therapy
In long-term therapy, periodic laboratory evaluation of organ systems, including
hematopoietic, renal, and hepatic studies should be performed.
7
6
ADVERSE REACTIONS
Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel,
particularly diarrhea, have been infrequent. The following adverse reactions have been
observed in patients receiving tetracyclines:
6.1
Gastrointestinal
Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and
inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity
has been reported rarely. These reactions have been caused by both the oral and
parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal
ulcerations have been reported in patients receiving capsule and tablet forms of drugs in
the tetracycline class. Most of these patients took medications immediately before going
to bed [see DOSAGE AND ADMINISTRATION (2.1)].
6.2
Skin
Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is
uncommon. Photosensitivity is discussed above [see WARNINGS AND
PRECAUTIONS (5.3)].
6.3
Renal
Rise in BUN has been reported and is apparently dose-related [see WARNINGS AND
PRECAUTIONS (5.7)].
6.4
Hypersensitivity reactions
Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness,
pericarditis, and exacerbation of systemic lupus erythematosus.
6.5
Blood
Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.
6.6
Benign Intracranial Hypertension
Bulging fontanels in infants and benign intracranial hypertension in adults [See
WARNINGS AND PRECAUTIONS (5.5)].
6.7
Thyroid Gland Changes
When given over prolonged periods, tetracyclines have been reported to produce brownblack microscopic discoloration of thyroid glands. No abnormalities of thyroid function
are known to occur.
7
DRUG INTERACTIONS
7.1
Anticoagulant Drugs
Because tetracyclines have been shown to depress plasma prothrombin activity, patients
who are on anticoagulant therapy may require downward adjustment of their
anticoagulant dosage.
8
7.2
Penicillin
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is
advisable to avoid giving tetracyclines in conjunction with penicillin.
7.3
Antacids and Iron Preparations
Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or
magnesium, bismuth subsalicylate, and iron-containing preparations.
7.4
Oral Contraceptives
Concurrent use of tetracycline may render oral contraceptives less effective.
7.5
Barbiturates and anti-epileptics
Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.
7.6
Penthrane
The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to
result in fatal renal toxicity.
7.7
Drug/Laboratory Test Interactions
False elevations of urinary catecholamines may occur due to interference with the
fluorescence test.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic Effects. Pregnancy Category D:
There are no adequate and well-controlled studies on the use of doxycycline in pregnant
women. The vast majority of reported experience with doxycycline during human
pregnancy is short-term, first trimester exposure. There are no human data available to
assess the effects of long-term therapy of doxycycline in pregnant women such as that
proposed for the treatment of anthrax exposure. An expert review of published data on
experiences with doxycycline use during pregnancy by TERIS - the Teratogen
Information System - concluded that therapeutic doses during pregnancy are unlikely to
pose a substantial teratogenic risk (the quantity and quality of data were assessed as
limited to fair), but the data are insufficient to state that there is no risk.1
A case-control study (18,515 mothers of infants with congenital anomalies and 32,804
mothers of infants with no congenital anomalies) shows a weak but marginally
statistically significant association with total malformations and use of doxycycline
anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the
cases were treated with doxycycline. This association was not seen when the analysis was
confined to maternal treatment during the period of organogenesis (i.e., in the second and
third months of gestation) with the exception of a marginal relationship with neural tube
defect based on only two-exposed cases.2
9
A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10
days with doxycycline during early first trimester. All mothers reported their exposed
infants were normal at 1 year of age.3
Nonteratogenic effects: [See WARNINGS AND PRECAUTIONS (5.1, 5.6)].
8.3
Nursing Mothers
Tetracyclines are excreted in human milk, however, the extent of absorption of
tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use
by lactating women is not necessarily contraindicated; however, the effects of prolonged
exposure to doxycycline in breast milk are unknown.4 Because of the potential for serious
adverse reactions in nursing infants from doxycycline, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother. [See WARNINGS AND PRECAUTIONS (5.1,
5.6).]
8.4
Pediatric use
Because of the effects of drugs of the tetracycline class on tooth development and
growth, DORYX should not be used in pediatric patients to the age of 8 years, except for
inhalational anthrax (post-exposure), unless other drugs are not likely to be effective or
are contraindicated. [See WARNINGS AND PRECAUTIONS (5.1, 5.6) and DOSAGE
AND ADMINISTRATION (2.1, 2.3).]
8.5
Geriatric use
Clinical studies of DORYX did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
DORYX 75 mg tablets contain 4.5 mg (0.196 mEq) of sodium.
DORYX 100 mg tablets contain 6 mg (0.261 mEq) of sodium.
DORYX 150 mg tablets contain 9 mg (0.392 mEq) of sodium.
8.6
Renal Impairment
Administration of doxycycline at the usual recommended dose does not result in
excessive accumulation in patients with renal impairment. Dosage adjustment is not
necessary in patients with renal impairment [see CLINICAL PHARMACOLOGY
(12)].
10.
OVERDOSAGE
In case of overdosage, discontinue medication, treat symptomatically and institute
supportive measures. Dialysis does not alter serum half-life and thus would not be of
benefit in treating cases of overdosage.
10
11.
DESCRIPTION
DORYX (doxycycline hyclate) Delayed-Release Tablets, for oral administration, contain
specially coated pellets of doxycycline hyclate, a broad-spectrum antibiotic synthetically
derived from oxytetracycline, in a delayed-release formulation for oral administration.
The structural formula for doxycycline hyclate is:
with a molecular formula of C22H24N2O8, HCl, ½ C2H6O, ½ H2O and a molecular weight
of 512.9. The chemical designation for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)]
-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6­
methyl-1,11-deoxonapthtacene-2-carboxamide monohydrochloride, compound with ethyl
alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder soluble
in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high
degree of lipid solubility and a low affinity for calcium binding. It is highly stable in
normal human serum. Doxycycline will not degrade into an epianhydro form. Inert
ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose;
sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch;
crospovidone; magnesium stearate; cellulosic polymer coating.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Doxycycline is an antimicrobial drug [see CLINICAL PHARMACOLOGY (12.4)].
12.3
Pharmacokinetics
Doxycycline is virtually completely absorbed after oral administration. Following
administration of a single 200 mg dose to adult volunteers, average peak serum
doxycycline levels were 2.6 mcg/mL at 2 hours, decreasing to 1.45 mcg/mL at 24 hours.
The mean Cmax and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively,
following single dose administration of DORYX tablets, 100 mg with a high fat meal
(including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19%
lower and the AUC 0-∞ is unchanged following single dose administration of DORYX
Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The
clinical significance of these decreases is unknown.
11
When DORYX Tablets are sprinkled over applesauce and taken with or without water,
the extent of doxycycline absorption is unchanged, but the rate of absorption is increased
slightly.
Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at
high concentrations and in a biologically active form. Excretion of doxycycline by the
kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75
mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a
creatinine clearance below 10 mL/min.
Studies have shown no significant difference in the serum half-life of doxycycline (range
18-22 hours) in individuals with normal and severely impaired renal function.
Hemodialysis does not alter the serum half-life.
12.4 Microbiology
The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial
effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline,
have a similar antimicrobial spectrum of activity against a wide range of gram-positive
and gram-negative organisms. Cross-resistance between tetracyclines is common.
Because isolates of the following gram-negative, gram-positive, anaerobic and other
microorganisms have been shown to be resistant to tetracyclines, culture and
susceptibility testing when possible is recommended prior to initiating therapy.
Gram-Negative Microorganisms
Acinetobacter species
Brucella species
Calymmatobacterium granulomatis
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella species
Neisseria gonorrhoeae
Shigella species
Vibrio Cholerae
Yersinia pestis
Gram-Positive Microorganisms
Alpha-hemolytic streptococci (viridans group)
Bacillus anthracis
Enterococcus faecalis
Enterococcus faecium
Streptococcus pyogenes
Streptococcus pneumoniae
12
Anerobic Microorganisms
Bacteroides species
Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes
Other Microorganisms
Actinomyces species
Bartonella bacilliformis
Borrelia recurrentis
Chlamydia psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae
Treponema pallidum
Treponema pertenue
Ureaplasma urealyticum
Parasites
Balantidium coli
Entamoeba species
Plasmodium falciparum
Doxycycline has been found to be active against the asexual erythrocytic forms of
Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise
mechanism of action of the drug is not known.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative results
of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and
practice areas to the physician as periodic reports that describe the susceptibility profile
of nosocomial and community-acquired pathogens. These reports should aid the
physician in selecting the most effective antimicrobial.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to
antimicrobial compounds. The MICs should be determined using a standardized
procedure based on dilution methods (broth, agar, or microdilution),5,7 or equivalent using
standardized inoculum and concentrations of doxycycline. The MIC values should be
interpreted according to the criteria provided in Table 1.
13
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide
reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The
standard procedure6,7 requires the use of standardized inoculum concentrations. This
procedure uses paper disks impregnated with 30 mcg doxycycline to test the
susceptibility of microorganisms to doxycycline. Interpretation involves the correlation of
the diameter obtained in the disk test with the MIC for doxycycline. Reports from the
laboratory providing results of the standard single-disk susceptibility test with a 30 mcg
doxycycline disk should be interpreted according to the criteria in Table 1:
Table 1 Susceptibility Test Interpretive Criteria for Doxycycline
Pathogen
Acinetobacter spp.
Enterobacteriaceae
Enterococcus
faecalis and
faecium
Vibrio cholerae
Yersinia pestis
Bacillus anthracisa
Brucella speciesa
Franciscella
tularensisa
Susceptibility Interpretive Criteria
Minimal Inhibitory
Concentration (mcg/mL)
I
R
<4
8
>16
<4
8
>16
>16
<4
<4
<4
<1
<1
<4
8
8
8
>16
>16
-
Disk Diffusion Zone
Diameter (mm) - 30 mcg disk
S
I
R
<9
10-12
>13
<10
11-13
>14
<12
>16
13-15
-
-
-
-
-
-
-
-
a
The current absence of resistance isolates precludes defining any results other than
“Susceptible”. Isolates yielding results other than susceptible should be subjected to
additional testing.
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the
antimicrobial compound reaches the concentrations usually achievable. A report of
“Intermediate” indicates that the result should be considered equivocal, and, if the
microorganism is not fully susceptible to alternative, clinically feasible drugs, the test
should be repeated. This category implies possible clinical applicability in body sites
where the drug is physiologically concentrated or in situations where high dosage of drug
can be used. This category also provides a buffer zone that prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report of
“Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial
compound reaches the concentrations usually achievable; other therapy should be
selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to
monitor and ensure the accuracy and precision of the supplies and reagents used in the
14
assay, and the techniques of the individuals performing the test.5,6,7 Standard doxycycline
powder should provide the MIC values provided in Table 2. For the diffusion technique
using the 30 mcg tigecycline disk the criteria provided in Table 2 should be achieved.
Table 2 Acceptable Quality Control Ranges for Doxycycline to be Used for Validation of
Susceptibility Test Results
Pathogen
Enterococcus faecalis ATCC
29212
Escherichia coli ATCC 25922
Staphylococcus aureus ATCC
25923
for Enterococcus spp.
Staphylococcus aureus ATCC
29213
for Enterococcus spp., B.
anthracis
and F. tularensis
Streptococcus pneumoniae
ATCC 49619 for Brucella spp.
Acceptable Quality Control
Ranges
Minimal Inhibitory
Concentration (mcg/mL)
2-8
Disk Diffusion Zone
Diameter (mm) - 30 mcg disk
NONE
0.5 - 2
18 - 24
Not Applicable
23 - 29
0.12 - 0.5
Not Applicable
0.015 - 0.12
Not Applicable
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NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not
been conducted. However, there has been evidence of oncogenic activity in rats in studies
with the related antibiotics, oxytetracycline (adrenal and pituitary tumors) and
minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline
have not been conducted, positive results in in vitro mammalian cell assays have been
reported for related antibiotics (tetracycline, oxytetracycline).
Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no
apparent effect on the fertility of female rats. Effect on male fertility has not been studied.
13.2 Animal Toxicology and/or Pharmacology
Hyperpigmentation of the thyroid has been produced by members of the tetracycline class
in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and
methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and
methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.
Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base,
oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet.
This goitrogenic effect was accompanied by high radioactive iodine uptake.
Administration of minocycline also produced a large goiter with high radioiodine uptake
in rats fed a relatively high iodine diet.
15
Treatment of various animal species with this class of drugs has also resulted in the
induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in
chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland
hyperplasia has been observed in goats and rats treated with oxytetracycline.
Results of animal studies indicate that tetracyclines cross the placenta and are found in
fetal tissues.
15
REFERENCES
1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians
(TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195.
2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol
1997; 89: 524-528.
3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive
pregnancies: a prospective study. Int J Fertil 1980; 25:315-317.
4. Hale T. Medications and Mothers Milk. 9th. edition. Amarillo, TX: Pharmasoft
Publishing 2000; 225-226.
5. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution
Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically – 7th ed. Approved
Standard, CLSI document M7-A7, Vol. 26. CLSI, Wayne, PA. January 2006.
6. CLSI. Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests –
9th ed. Approved Standard, CLSI document M2-A9, Vol. 26. CLSI, Wayne, PA. January
2006.
7. CLSI. Performance Standards for Antimicrobial Susceptibility Testing – 18th
Informational Supplement. Approved Standard, CLSI document M100-S18, Vol. 28.
CLSI, Wayne, PA. January 2008.
16
HOW SUPPLIED/STORAGE AND HANDLING
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 75 mg: Bottles of 60 tablets
N 0430-0111-20
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 100 mg: Bottles of 100 tablets
N 0430-0112-24
DORYX® (doxycycline hyclate) Delayed-Release Tablets, 150 mg: Bottles of 60 tablets
N 0430-0113-20
Store at 25° C (77° F); excursions permitted to 15° - 30° C (59° - 86° F) [see USP
Controlled Room Temperature]; dispense in a tight, light-resistant container (USP).
16
17
PATIENT COUNSELING INFORMATION
Patients taking doxycycline for malaria prophylaxis should be advised:
• that no present-day antimalarial agent, including doxycycline, guarantees protection
against malaria.
• to avoid being bitten by mosquitoes by using personal protective measures that help
avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in wellscreened areas, using mosquito nets, covering the body with clothing, and using an
effective insect repellant).
• that doxycycline prophylaxis:
• should begin 1-2 days before travel to the malarious area,
• should be continued daily while in the malarious area and after leaving the
malarious area,
• should be continued for 4 further weeks to avoid development of malaria after
returning from an endemic area,
• should not exceed 4 months.
All patients taking doxycycline should be advised:
• to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline
and to discontinue therapy if phototoxicity (e.g., skin eruptions, etc.) occurs.
Sunscreen or sunblock should be considered [See WARNINGS AND
PRECAUTIONS (5.6)].
• to drink fluids liberally along with doxycycline to reduce the risk of esophageal
irritation and ulceration [See ADVERSE REACTIONS (6.1)].
• that the absorption of tetracyclines is reduced when taken with foods, especially those
that contain calcium. However, the absorption of doxycycline is not markedly
influenced by simultaneous ingestion of food or milk [See DRUG INTERACTIONS
(7.3)].
• that the absorption of tetracyclines is reduced when taken with antacids containing
aluminum, calcium or magnesium, bismuth subsalicylate, and iron containing
preparations [See DRUG INTERACTIONS (7.4)].
• that the use of doxycycline might increase the incidence of vaginal candidiasis.
Diarrhea is a common problem caused by antibiotics which usually ends when the
antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients
can develop watery and bloody stools (with or without stomach cramps and fever) even
as late as two or more months after having taken the last dose of antibiotic. If this occurs,
patients should contact their physician as soon as possible.
Patients should be counseled that antibacterial drugs including DORYX should only be
used to treat bacterial infections. They do not treat viral infections (e.g., the common
cold). When DORYX is prescribed to treat a bacterial infection, patients should be told
that although it is common to feel better early in the course of therapy, the medication
should be taken exactly as directed. Skipping doses or not completing the full course of
therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase
17
the likelihood that bacteria will develop resistance and will not be treatable by DORYX
or other antibacterial drugs in the future.
Rx only
U.S. Patent No: 6,958,161
Manufactured by:
Mayne Pharma International Pty Ltd
1538 Main North Road
Salisbury South, South Australia 5106
Marketed by:
Warner Chilcott (US), LLC
Rockaway, NJ 07866
1-800-521-8813
0112G035
Revised June 2008
18